Cystic fibrosis (CF) is a common lethal genetic disorder affecting approximately 1 in 2000 Caucasians.sup.1. The major pathological manifestations in CF are obstruction of pulmonary, gastrointestinal and pancreatobiliary ducts by accumulation of mucoid secretions ultimately leading to organ failure, particularly in the lung. The basic cellular defect in CF is abnormal chloride transport due to mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.sup.2-7. The CFTR gene encodes a protein required for the normal function of a cAMP regulated chloride channel present in secretory and other cells throughout the body. Despite rapid advances in our knowledge of the structure and function of CFTR, the cellular and physiological basis of the mucus abnormalities in CF remain obscure.
Liver disease is the second leading cause of death in CF, after lung disease .sup.8,9. The major hepatic manifestation of CF is a distinct form of focal biliary cirrhosis, a condition that may be accompanied or preceded by inspissated cosinophilic material resembling the mucoid material found in other organs of CF patients.sup.10. Approximately 20% of surviving adolescents and adults with CF have morphologic evidence of liver disease, and about 10 to 15% of these develop complications of fibrosis, cirrhosis and portal hypertension requiring transplantation.sup.11. Other manifestations of biliary tract disease in CF include biliary sludge and casts, increased incidence of gallstones and common bile duct strictures. Very little is known of the pathogenesis of hepatobiliary disease in CF, and detailed analysis of the inspissated material plugging bile ductules has not been published. The abnormalities in biliary secretion are assumed to be related to the known single gene defect in CF, mutation of the CFTR. Recent studies by Cohen et al.sup.12 have documented that CFTR is localized in liver exclusively to the apical membrane of bile duct cells, but not in hepatocytes. This suggests that the hepatobiliary abnormalities in CF, particularly focal biliary cirrhosis, originate in bile duct cells, possibly by dysregulation of glycoprotein synthesis.
The availability of immortalized human intrahepatic biliary epithelial cells from normal and CF patients allow direct comparison of synthesis and secretion of biliary macromolecules in vitro.